{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T12:02:42Z","timestamp":1790510562922,"version":"4.1.0"},"reference-count":87,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2019,3,19]],"date-time":"2019-03-19T00:00:00Z","timestamp":1552953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF17SA0028700"],"award-info":[{"award-number":["NNF17SA0028700"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003554","name":"Lundbeckfonden","doi-asserted-by":"publisher","award":["R262-2017-2300"],"award-info":[{"award-number":["R262-2017-2300"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Snake venom metalloproteinases (SVMPs) and snake venom serine proteinases (SVSPs) are among the most abundant enzymes in many snake venoms, particularly among viperids. These proteinases are responsible for some of the clinical manifestations classically seen in viperid envenomings, including hemorrhage, necrosis, and coagulopathies. The objective of this study was to investigate the enzymatic activities of these proteins using a high-throughput peptide library to screen for the proteinase targets of the venoms of five viperid (Echis carinatus, Bothrops asper, Daboia russelii, Bitis arietans, Bitis gabonica) and one elapid (Naja nigricollis) species of high medical importance. The proteinase activities of these venoms were each tested against 360 peptide substrates, yielding 2160 activity profiles. A nonlinear regression model that accurately described the observed enzymatic activities was fitted to the experimental data, allowing for the comparison of cleavage rates across species. In this study, previously unknown protein targets of snake venom proteinases were identified, potentially implicating novel human and animal proteins that may be involved in the pathophysiology of viper envenomings. The functional relevance of these targets was further evaluated and discussed. These new findings may contribute to our understanding of the clinical manifestations and underlying biochemical mechanisms of snakebite envenoming by viperid species.<\/jats:p>","DOI":"10.3390\/toxins11030170","type":"journal-article","created":{"date-parts":[[2019,3,19]],"date-time":"2019-03-19T12:12:25Z","timestamp":1552997545000},"page":"170","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Protease Activity Profiling of Snake Venoms Using High-Throughput Peptide Screening"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3907-9281","authenticated-orcid":false,"given":"Konstantinos","family":"Kalogeropoulos","sequence":"first","affiliation":[{"name":"Department of Biotechnology and Biomedicine, Technical University of Denmark, 2800 Lyngby, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Treschow","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biomedicine, Technical University of Denmark, 2800 Lyngby, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3431-7415","authenticated-orcid":false,"given":"Ulrich","family":"auf dem Keller","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biomedicine, Technical University of Denmark, 2800 Lyngby, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Escalante","sequence":"additional","affiliation":[{"name":"Instituto Clodomiro Picado, Facultad de Microbiolog\u00eda, Universidad de Costa Rica, San Jos\u00e9 11501-2060, Costa Rica"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Rucavado","sequence":"additional","affiliation":[{"name":"Instituto Clodomiro Picado, Facultad de Microbiolog\u00eda, Universidad de Costa Rica, San Jos\u00e9 11501-2060, Costa Rica"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8385-3081","authenticated-orcid":false,"given":"Jos\u00e9","family":"Guti\u00e9rrez","sequence":"additional","affiliation":[{"name":"Instituto Clodomiro Picado, Facultad de Microbiolog\u00eda, Universidad de Costa Rica, San Jos\u00e9 11501-2060, Costa Rica"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6918-5574","authenticated-orcid":false,"given":"Andreas","family":"Laustsen","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biomedicine, Technical University of Denmark, 2800 Lyngby, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2210-3743","authenticated-orcid":false,"given":"Christopher","family":"Workman","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biomedicine, Technical University of Denmark, 2800 Lyngby, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,3,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4544","DOI":"10.1111\/j.1742-4658.2011.08115.x","article-title":"Enzymatic toxins from snake venom: Structural characterization and mechanism of catalysis","volume":"278","author":"Kang","year":"2011","journal-title":"FEBS J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.toxicon.2012.09.008","article-title":"Non-enzymatic proteins from snake venoms: A gold mine of pharmacological tools and drug leads","volume":"62","author":"McCleary","year":"2013","journal-title":"Toxicon"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.jprot.2014.02.020","article-title":"Venomous snakes of Costa Rica: Biological and medical implications of their venom proteomic profiles analyzed through the strategy of snake venomics","volume":"105","author":"Lomonte","year":"2014","journal-title":"J. Proteom."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.jprot.2017.03.003","article-title":"Functional proteomic analyses of Bothrops atrox venom reveals phenotypes associated with habitat variation in the Amazon","volume":"159","author":"Sousa","year":"2017","journal-title":"J. Proteom."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jprot.2016.10.006","article-title":"Proteomic analysis of venom variability and ontogeny across the arboreal palm-pitvipers (genus Bothriechis)","volume":"152","author":"Pla","year":"2017","journal-title":"J. Proteom."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3370","DOI":"10.1021\/acs.jproteome.7b00414","article-title":"Integrated Venomics and Venom Gland Transcriptome Analysis of Juvenile and Adult Mexican Rattlesnakes Crotalus simus, C. tzabcan, and C. culminatus Revealed miRNA-modulated Ontogenetic Shifts","volume":"16","author":"Durban","year":"2017","journal-title":"J. Proteome Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1515\/amma-2015-0114","article-title":"Snake Venom Metalloproteinases","volume":"62","author":"Kelemen","year":"2016","journal-title":"Acta Medica Marisiensis"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1002\/jmr.1091","article-title":"Looking at the proteases from a simple perspective","volume":"24","author":"Castro","year":"2011","journal-title":"J. Mol. Recognit."},{"key":"ref_9","unstructured":"Mackessy, S.P. (2010). Snake venom metalloproteinases. Biological roles and participation in the pathophysiology of envenomation. Handbook of Venoms and Toxins of Reptiles, CRC Press."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"17063","DOI":"10.1038\/nrdp.2017.63","article-title":"Snakebite envenoming","volume":"3","author":"Calvete","year":"2017","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Takeda, S. (2016). ADAM and ADAMTS family proteins and snake venom metalloproteinases: A structural overview. Toxins, 8.","DOI":"10.3390\/toxins8050155"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"595186","DOI":"10.1155\/2014\/595186","article-title":"Isolation and biochemical characterization of a new thrombin-like serine protease from Bothrops pirajai snake venom","volume":"2014","author":"Zaqueo","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1016\/j.toxicon.2005.02.020","article-title":"Snake venom serine proteinases: Sequence homology vs. substrate specificity, a paradox to be solved","volume":"45","author":"Serrano","year":"2005","journal-title":"Toxicon"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1016\/j.biochi.2012.07.007","article-title":"Biochemical characterization and comparative analysis of two distinct serine proteases from Bothrops pirajai snake venom","volume":"94","author":"Menaldo","year":"2012","journal-title":"Biochimie"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"D624","DOI":"10.1093\/nar\/gkx1134","article-title":"The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database","volume":"46","author":"Rawlings","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.bbapap.2011.04.009","article-title":"Snake venom metalloproteinases: Structure, function and relevance to the mammalian ADAM\/ADAMTS family proteins","volume":"1824","author":"Takeda","year":"2012","journal-title":"BBA-Proteins Proteom."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1016\/j.toxicon.2005.02.012","article-title":"Structural considerations of the snake venom metalloproteinases, key members of the M12 reprolysin family of metalloproteinases","volume":"45","author":"Fox","year":"2005","journal-title":"Toxicon"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.jprot.2017.05.024","article-title":"Serine protease isoforms in Gloydius intermedius venom: Full sequences, molecular phylogeny and evolutionary implications","volume":"164","author":"Yang","year":"2017","journal-title":"J. Proteom."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.bbrc.2004.09.031","article-title":"A novel P-I class metalloproteinase with broad substrate-cleaving activity, agkislysin, from Agkistrodon acutus venom","volume":"324","author":"Wang","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1177\/1535370216660214","article-title":"Biochemical and biological characterization of Bothriechis schlegelii snake venoms from Colombia and Costa Rica","volume":"241","author":"Kimura","year":"2016","journal-title":"Exp. Biol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.biochi.2014.06.015","article-title":"Fibrin(ogen)olytic and platelet modulating activity of a novel protease from the Echis multisquamatis snake venom","volume":"105","author":"Chernyshenko","year":"2014","journal-title":"Biochimie"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.3892\/ijmm.2014.1864","article-title":"Purification and biochemical characterization of a fibrin(ogen)olytic metalloprotease from Macrovipera mauritanica snake venom which induces vascular permeability","volume":"34","author":"Lee","year":"2014","journal-title":"Int. J. Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.jprot.2010.12.002","article-title":"High resolution analysis of snake venom metalloproteinase (SVMP) peptide bond cleavage specificity using proteome based peptide libraries and mass spectrometry","volume":"74","author":"Escalante","year":"2011","journal-title":"J. Proteom."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.jprot.2014.10.002","article-title":"Snake venom serine proteinases specificity mapping by proteomic identification of cleavage sites","volume":"113","author":"Zelanis","year":"2015","journal-title":"J. Proteom."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4553","DOI":"10.3390\/s130404553","article-title":"Internal calibration f\u00f6rster resonance energy transfer assay: A real-time approach for determining protease kinetics","volume":"13","author":"Jiang","year":"2013","journal-title":"Sensors"},{"key":"ref_26","unstructured":"Zhang, G. (2018, July 06). Protease Assays, Assay Guidance Manual, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK92006\/."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"10788","DOI":"10.1074\/jbc.M011772200","article-title":"Reaction kinetics of protease with substrate phage: Kinetic model developed using stromelysin","volume":"276","author":"Sharkov","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_28","first-page":"1","article-title":"Quantitative F\u00f6rster Resonance Energy Transfer Analysis for SENP1 Protease Kinetics Determination","volume":"28","author":"Liu","year":"2013","journal-title":"J. Vis. Exp."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1021\/pr101040f","article-title":"Snake Venomics of African Spitting Cobras: Toxin Composition and Assessment of Congeneric Cross-Reactivity of the Pan-African EchiTAb-Plus-ICP Antivenom by Antivenomics and Neutralization Approaches","volume":"10","author":"Petras","year":"2011","journal-title":"J. Proteome Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Figueroa, A., McKelvy, A.D., Grismer, L.L., Bell, C.D., and Lailvaux, S.P. (2016). A species-level phylogeny of extant snakes with description of a new colubrid subfamily and genus. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0161070"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"40827","DOI":"10.1074\/jbc.M006234200","article-title":"The isolation, characterization, and molecular cloning of a 75-kDa gelatinase B-like enzyme, a member of the matrix metalloproteinase (MMP) family: An avian enzyme that is MMP-9-like in its cell expression pattern but diverges from mammalian gelatinase B","volume":"275","author":"Aimes","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1016\/j.biochi.2012.02.006","article-title":"Alsophinase, a new P-III metalloproteinase with \u03b1-fibrinogenolytic and hemorrhagic activity from the venom of the rear-fanged Puerto Rican Racer Alsophis portoricensis (Serpentes: Dipsadidae)","volume":"94","author":"Weldon","year":"2012","journal-title":"Biochimie"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/jbt.21835","article-title":"Biochemical and biological characterization of a dermonecrotic metalloproteinase isolated from Cerastes cerastes snake venom","volume":"31","author":"Ami","year":"2017","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1161\/CIRCGENETICS.112.964452","article-title":"Proteomic identification of matrix metalloproteinase substrates in the human vasculature","volume":"6","author":"Stegemann","year":"2013","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1007\/s00726-016-2218-z","article-title":"Proteome-derived peptide library for the elucidation of the cleavage specificity of HF3, a snake venom metalloproteinase","volume":"48","author":"Bertholim","year":"2016","journal-title":"Amino Acids"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"588","DOI":"10.5483\/BMBRep.2013.46.12.081","article-title":"Identification of the novel substrates for caspase-6 in apoptosis using proteomic approaches","volume":"46","author":"Cho","year":"2013","journal-title":"BMB Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"47","DOI":"10.3892\/ijmm.2017.2984","article-title":"Identification of candidate substrates of ubiquitin-specific protease 13 using 2D-DiGE","volume":"40","author":"Wang","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1016\/j.bbagen.2012.07.011","article-title":"BJ-PI2, A non-hemorrhagic metalloproteinase from Bothrops jararaca snake venom","volume":"1820","author":"Lorenzetti","year":"2012","journal-title":"BBA-Gen. Subj."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/978-1-4939-6863-3_9","article-title":"Time-Resolved Analysis of Matrix Metalloproteinase Substrates in Complex Samples","volume":"Volume 1579","author":"Schlage","year":"2017","journal-title":"Matrix Metalloproteases: Methods and Protocols, Methods in Molecular Biology"},{"key":"ref_40","first-page":"1","article-title":"A bead-based cleavage method for large-scale identification of protease substrates","volume":"6","author":"Wang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1038\/nbt1408","article-title":"Proteome-derived, database-searchable peptide libraries for identifying protease cleavage sites","volume":"26","author":"Schilling","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.toxicon.2012.09.004","article-title":"Snake venom metalloproteinases","volume":"62","author":"Markland","year":"2013","journal-title":"Toxicon"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.toxicon.2012.09.003","article-title":"The long road of research on snake venom serine proteinases","volume":"62","author":"Serrano","year":"2013","journal-title":"Toxicon"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1016\/j.toxicon.2005.02.025","article-title":"Snake venom probes of platelet adhesion receptors and their ligands","volume":"45","author":"Wijeyewickrema","year":"2005","journal-title":"Toxicon"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.vph.2004.02.004","article-title":"Integrin \u03b24 is a target of rattlesnake venom during inducing apoptosis of vascular endothelial cells","volume":"41","author":"Zhao","year":"2004","journal-title":"Vascul. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.toxicon.2015.03.019","article-title":"Elucidation of procoagulant mechanism and pathophysiological significance of a new prothrombin activating metalloprotease purified from Daboia russelii russelii venom","volume":"100","author":"Thakur","year":"2015","journal-title":"Toxicon"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/j.molimm.2010.07.003","article-title":"Human complement activation and anaphylatoxins generation induced by snake venom toxins from Bothrops genus","volume":"47","author":"Filgueiras","year":"2010","journal-title":"Mol. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1080\/09629350020025728","article-title":"Bothrops asper snake venom and its metalloproteinase BaP-1 activate the complement system. Role in leucocyte recruitment","volume":"9","author":"Farsky","year":"2000","journal-title":"Mediators Inflamm."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2164-10-564","article-title":"Comparative venom gland transcriptome surveys of the saw-scaled vipers (Viperidae: Echis) reveal substantial intra-family gene diversity and novel venom transcripts","volume":"10","author":"Casewell","year":"2009","journal-title":"BMC Genom."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.toxicon.2016.10.007","article-title":"Development of a new polyspecific antivenom for snakebite envenoming in Sri Lanka: Analysis of its preclinical efficacy as compared to a currently available antivenom","volume":"122","author":"Villalta","year":"2016","journal-title":"Toxicon"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1016\/j.toxicon.2009.06.011","article-title":"Studies on the venom proteome of Bothrops asper: Perspectives and applications","volume":"54","author":"Sanz","year":"2009","journal-title":"Toxicon"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1016\/j.toxicon.2010.07.001","article-title":"Preclinical assessment of the neutralizing capacity of antivenoms produced in six Latin American countries against medically-relevant Bothrops snake venoms","volume":"56","author":"Segura","year":"2010","journal-title":"Toxicon"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1007\/s00239-005-0268-z","article-title":"Molecular cloning of disintegrin-like transcript BA-5A from a Bitis arietans venom gland cDNA library: A putative intermediate in the evolution of the long-chain disintegrin bitistatin","volume":"63","author":"Wagstaff","year":"2006","journal-title":"J. Mol. Evol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.toxicon.2009.08.010","article-title":"Preclinical assessment of the efficacy of a new antivenom (EchiTAb-Plus-ICP\u00ae) for the treatment of viper envenoming in sub-Saharan Africa","volume":"55","author":"Segura","year":"2010","journal-title":"Toxicon"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2732","DOI":"10.1021\/pr0701714","article-title":"Snake Venomics of Bitis Species Reveals Large Intragenus Venom Toxin Composition Variation:\u2009 Application to Taxonomy of Congeneric Taxa","volume":"6","author":"Calvete","year":"2007","journal-title":"J. Proteome Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.jprot.2016.06.001","article-title":"A proteomic analysis of Pakistan Daboia russelii russelii venom and assessment of potency of Indian polyvalent and monovalent antivenom","volume":"144","author":"Mukherjee","year":"2016","journal-title":"J. Proteom."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.trstmh.2004.09.014","article-title":"Pan-African polyspecific antivenom produced by caprylic acid purification of horse IgG: An alternative to the antivenom crisis in Africa","volume":"99","author":"Rojas","year":"2005","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3556","DOI":"10.1021\/pr800332p","article-title":"Snake Venomics of the Lancehead Pitviper Bothrops asper: Geographic, Individual, and Ontogenetic Variations research articles","volume":"7","author":"Sanz","year":"2008","journal-title":"J. Proteome Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.jprot.2013.05.024","article-title":"Intraspecies variation in the venom of the rattlesnake Crotalus simus from Mexico: Different expression of crotoxin results in highly variable toxicity in the venoms of three subspecies","volume":"87","author":"Castro","year":"2013","journal-title":"J. Proteom."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.toxicon.2015.07.008","article-title":"Danger in the reef: Proteome, toxicity, and neutralization of the venom of the olive sea snake, Aipysurus laevis","volume":"107","author":"Laustsen","year":"2015","journal-title":"Toxicon"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.toxicon.2018.07.019","article-title":"Snake Venomics Display: An online toolbox for visualization of snake venomics data","volume":"152","author":"Dam","year":"2018","journal-title":"Toxicon"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1016\/S0041-0101(98)00126-3","article-title":"Snake venoms and the hemostatic system","volume":"36","author":"Markland","year":"1998","journal-title":"Toxicon"},{"key":"ref_63","unstructured":"Barrett, A.J., Rawlings, N.D., and Woessner, J.F. (2004). Ecarin. Handbook of Proteolytic Enzymes, Elsevier."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"5200","DOI":"10.1074\/jbc.271.9.5200","article-title":"Isolation and characterization of carinactivase, a novel prothrombin activator in Echis carinatus venom with a unique catalytic mechanism","volume":"271","author":"Yamada","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S0167-4838(99)00236-8","article-title":"MALDI-TOF mass spectrometry analysis of substrate specificity of lebetase, a direct-acting fibrinolytic metalloproteinase from Vipera lebetina snake venom","volume":"1476","author":"Trummal","year":"2000","journal-title":"Biochim. Biophys. Acta."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0003-9861(03)00385-0","article-title":"Characterization of \u201cbasparin A,\u201d a prothrombin-activating metalloproteinase, from the venom of the snake Bothrops asper that inhibits platelet aggregation and induces defibrination and thrombosis","volume":"418","author":"Rucavado","year":"2003","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S0041-0101(99)00127-0","article-title":"Purification and characterization of BaH4, a hemorrhagic metalloproteinase from the venom of the snake Bothrops asper","volume":"38","author":"Franceschi","year":"2000","journal-title":"Toxicon"},{"key":"ref_68","unstructured":"Barrett, A.J., Rawlings, N.D., and Woessner, J.F. (2004). Venombin AB. Handbook of Proteolytic Enzymes, Elsevier."},{"key":"ref_69","unstructured":"Barrett, A.J., Rawlings, N.D., and Woessner, J.F. (2004). Russelysin. Handbook of Proteolytic Enzymes, Elsevier."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/j.toxicon.2005.02.030","article-title":"Snake venoms and coagulopathy","volume":"45","author":"White","year":"2005","journal-title":"Toxicon"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2000","DOI":"10.1002\/eji.1830260905","article-title":"Processing of pro-tumor necrosis factor-\u03b1 by venom metalloproteinases: A hypothesis explaining local tissue damage following snake bite","volume":"26","author":"Laing","year":"1996","journal-title":"Eur. J. Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.molimm.2014.06.020","article-title":"Animal venoms\/toxins and the complement system","volume":"61","author":"Tambourgi","year":"2014","journal-title":"Mol. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Guti\u00e9rrez, J.M., Escalante, T., Rucavado, A., Herrera, C., and Fox, J.W. (2016). A comprehensive view of the structural and functional alterations of extracellular matrix by snake venom metalloproteinases (SVMPs): Novel perspectives on the pathophysiology of envenoming. Toxins, 8.","DOI":"10.3390\/toxins8100304"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2421","DOI":"10.1038\/jid.2008.118","article-title":"Skin pathology induced by snake venom metalloproteinase: Acute damage, revascularization, and re-epithelization in a mouse ear model","volume":"128","author":"Escalante","year":"2008","journal-title":"J. Invest. Dermatol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Rucavado, A., Nicolau, C.A., Escalante, T., Kim, J., Herrera, C., Guti\u00e9rrez, J.M., and Fox, J.W. (2016). Viperid envenomation wound exudate contributes to increased vascular permeability via a DAMPs\/TLR-4 mediated pathway. Toxins, 8.","DOI":"10.3390\/toxins8120349"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Sanchez, E.F., Flores-Ortiz, R.J., Alvarenga, V.G., and Eble, J.A. (2017). Direct fibrinolytic snake venom metalloproteinases affecting hemostasis: Structural, biochemical features and therapeutic potential. Toxins, 9.","DOI":"10.3390\/toxins9120392"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3030","DOI":"10.1007\/s00018-006-6315-0","article-title":"Snake venom components and their applications in biomedicine","volume":"63","author":"Koh","year":"2006","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_78","unstructured":"Python Software Foundation (2018, November 01). Python Language Reference. Available online: https:\/\/www.python.org\/."},{"key":"ref_79","unstructured":"Oliphant, T.E. (2006). A guide to NumPy, Trelgol Publishing. [1st ed.]."},{"key":"ref_80","unstructured":"McKinney, W. (July, January 28). Data Structures for Statistical Computing in Python. Proceedings of the 9th Python in Science Conference, Austin, TX, USA."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1109\/MCSE.2007.55","article-title":"Matplotlib: A 2D Graphics Environment","volume":"9","author":"Hunter","year":"2007","journal-title":"Comput. Sci. Eng."},{"key":"ref_82","unstructured":"Waskom, M., Botvinnik, O., O\u2019Kane, D., Hobson, P., Lukauskas, S., Gemperline, D.C., Augspurger, T., Halchenko, Y., Cole, J.B., and Warmenhoven, J. (2018, December 15). mwaskom\/seaborn: v0.8.0 (July 2017). Available online: https:\/\/zenodo.org\/record\/824567#.XItk_poRWUk."},{"key":"ref_83","unstructured":"Jones, E., Oliphant, T., and Peterson, P. (2018, July 06). SciPy: Open source scientific tools for Python. Available online: https:\/\/www.scipy.org\/."},{"key":"ref_84","unstructured":"Seabold, S., and Perktold, J. (July, January 28). Statsmodels: Econometric and Statistical Modeling with Python. Proceedings of the 9th Python in Science Conference, Austin, TX, USA."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1748-7188-8-23","article-title":"Jaccard index based similarity measure to compare transcription factor binding site models","volume":"8","author":"Vorontsov","year":"2013","journal-title":"Algorithms Mol. Biol."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Deshpande, R., VanderSluis, B., and Myers, C.L. (2013). Comparison of Profile Similarity Measures for Genetic Interaction Networks. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0068664"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Huerta-Cepas, J., Dopazo, J., and Gabald\u00f3n, T. (2010). ETE: A python Environment for Tree Exploration. 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